MOD is the fourth leading causes of morbidity and mortality world-wide, with women having twice the incidence than men. We are proposing a translational SCOR to integrate scientists from basic, clinical neuroscience and population-level perspectives to address the question of why women are at higher risk for major depressive disorder (MOD) than men. Our underlying premise is that sex differences in adult MOD are initiated during mid-gestation, a period of Hypothalamic-Pituitary-Adrenal axis (HPA) circuitry development, sexual differentiation of the brain, and a period in which fetal risk factors for MOD have been identified. We will test hypotheses regarding the roles of adrenal and gonadal signaling pathways regulating BDNF and its interactions with GABA-ergic, GLU-tamatergic, and nitric oxide (NO) mechanisms in the development of regions in stress response circuitry. Project 1, a human in-vivo study of 500 DSM-IV MOD cases and 500 normal controls from a birth cohort (followed from prenatal development to age 47) will test for genetic polymorphisms associated with these pathways and maternal serum assessment of HPA abnormalities during mid-gestation to understanding sex differences in MOD. 40 recurrent cases matched to 40 normal controls will be re-recruited for functional brain imaging of stress response circuitry and neuroendocrine evaluations to test our hypotheses relating abnormal maternal-fetal HPA environment and genetic polymorphisms with sex differences in adult HPA dysfunction and stress response circuitry deficits. Project 2 consists of mouse models of developmental morphology and adult behavior regarding genetic and/or hormonal sex differences in embryonic HPA circuitry neurogenesis, cell migration, and cell death and the impact of these hormones and/or genes on sex differences in adult MOD phenotypic behavior analogous to human studies. Project 3 uses rat models to study morphological and adult endocrine outcomes, after fetal and neonatal glucocorticoid treatment on sex differences in developing HPA circuitry and adult sex differences in hormonal dysregulation and MOD phenotypic behavior. This includes the role of epigenetic factors resulting from early adverse glucocorticoid exposure. Our interdisciplinary teams of senior preclinical and clinical investigators, who collaborate with each other, have spent their careers studying the roles of hormones and genes in understanding sex differences in the brain, neuroendocrine deficits, and/or the treatment of MOD. To accomplish the integration of SCOR projects, we propose an Administrative Core. Thus the SCOR would provide support to formalize our collaborations to focus on a problem of major public health significance that has etiologic implications, particularly for women, and will provide knowledge for development of sex-specific treatment and prevention strategies.